Benzimidazole derivatives as RLK and ITK inhibitors

Abstract

The present disclosure is directed to certain inhibitors of RLK and ITK of formula (I), pharmaceutical compositions comprising such compounds, and method of treating diseases mediated by inhibition of RLK and ITK.

We claim: 
     
       1. A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 wherein: 
 
       Z 1 , Z 2 , and Z 3  are independently CH, or CR 2 ;
 R 1 is hydrogen, or -(alkylene)-NR 3 R 5 , where R 3  is hydrogen, alkyl, or cycloalkyl, and R 5  is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, acyl, cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, heterocyclyl, or heterocyclylalkyl wherein the heterocyclyl ring in heterocyclyl and heterocyclylalkyl is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, or alkoxyalkyl; or R 3  and R 5  together with the nitrogen atom to which they are attached form heterocycloamino or spiroheterocycloamino wherein the heterocycloamino ring is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxyl, alkoxy, hydroxyalkyl, or alkoxyalkyl; 
 R 2  is hydrogen, or alkyl; 
 —Ar—Ar 1  is: 
 
       
         
           
           
               
               
           
         
         X is a moiety of formula II, where Z is alkylene, and ring A is heterocycloamino optionally substituted with one or two substituents independently selected from alkyl, hydroxy, or fluoro or -(alkylene)-NR a — where R a  is hydrogen; 
       
       
         
           
           
               
               
           
         
         Y is —CO—; 
         R b  is hydrogen, or cyano; 
         R c  is hydrogen, or alkyl; and 
         R d  is hydrogen, or alkyl; 
         provided, however, when R b  is cyano, then R d  is hydrogen but R c  is not hydrogen. 
       
     
     
       2. The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein the compound of Formula (I) has the structure (Ia): 
       
         
           
           
               
               
           
         
       
     
     
       3. The compound of  claim 1  or a pharmaceutically acceptable a salt thereof wherein R b  is cyano and R c  is alkyl. 
     
     
       4. The compound of  claim 3  or a pharmaceutically acceptable salt thereof wherein R c  is isopropyl or tert-butyl. 
     
     
       5. The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein X is a moiety of formula II 
       
         
           
           
               
               
           
         
       
     
     
       6. The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein X is 
       
         
           
           
               
               
           
         
       
     
     
       7. The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein R 1  is —(CH 2 )—NHR 5  where R 5  is 2,2-dimethylpropyl, 2-methylpropyl, cyclopropylmethyl, —CH 2 C(CH 3 ) 2 OH, (R)-CH(CH 2 OH)C(CH 3 ) 3 , (S)-CH(CH 2 OH)C(CH 3 ) 3 , (R)-CH(CH 2 OH)CH 3 , (S)-CH(CH 2 OH)CH 3 , (R)-CH(CH 2 OCH 3 )CH 3 , (S)-CH(CH 2 OCH 3 )CH 3 , (S)-CH(CH 3 )C(CH 3 ) 3 , (R)-CH(CH 3 )C(CH 3 ) 3 , tetrahydrofuran-4-yl, 2,2-difluoroethyl, tetrahydropyran-3-yl, oxazol-2-ylmethyl, thiazol-2-ylmethyl, tetrahydrofuran-2-ylmethyl, morpholin-4-ylmethyl. 
     
     
       8. The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein R 1  is: 
       
         
           
           
               
               
           
         
       
     
     
       9. A compound selected from the group consisting of:
 (R)-N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 (R)-N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((cyclopropyl-methyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-1-hydroxy-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((R)-1-hydroxy-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-1-hydroxypropan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((R)-1-hydroxypropan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((R)-1-methoxypropan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-1-methoxypropan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 (R)-N-(1-((1-acryloylpyrrolidin-2-yl)methyl)-5-(((cyclopropylmethyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-acryloylpyrrolidin-2-yl)methyl)-5-((((S)-1-hydroxy-3,3-dimethylbutan-2-yl)amino)methyl)-1 H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-acryloylpyrrolidin-2-yl)methyl)-5-((((R)-1-hydroxy-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-acryloylpyrrolidin-2-yl)methyl)-5-((((S)-1-hydroxypropan-2-yl)amino)methyl)-1H-benzo [d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-acryloylpyrrolidin-2-yl)methyl)-5-((((R)-1-hydroxypropan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 (R)-N-(1-((1-acryloylpyrrolidin-2-yl)methyl)-5-(((2-hydroxy-2-methylpropyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 (R)-N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((2-hydroxy-2-methylpropyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 (R)-N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((tetrahydro-2H-pyran-4-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 (R)-N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((2,2-difluoroethyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((S)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((tetrahydrofuran-3-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 (R)-N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(1-hydroxy-3-methylbutyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 (R)-N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((isobutyl-amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 (R)-N-(1-((1-(2-cyano-3-cyclopropylacryloyl)pyrrolidin-2-yl)methyl)-5-(((cyclopropyl-methyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 (R)-N-(1-((1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((cyclopropyl-methyl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 (R)-N-(1-((1-(2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((neopentylamino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-(1-(((R)-1-acryloylpyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(2-fluoropyridin-4-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-3-cyclopropylacryloyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((cyclopropylmethyl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(2-fluoropyridin-4-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(2-methyloxazol-5-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-1-methoxypropan-2-yl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((cyclopropylmethyl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazo 2-ylidene)-5-(2-methyloxazol-5-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(1H-pyrazol-1-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-3-(1-methylcyclopropyl)acryloyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-3-cyclopropylacryloyl)pyrrolidin-2-yl)methyl)-5-(((2-hydroxy-2-methylpropyl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((cyclopropylmethyl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(1H-pyrazol-1-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((cyclopropylmethyl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(1H-1,2,4-triazol-1-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(1H-1,2,4-triazol-1-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(pyrimidin-4-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-3-cyclopropylacryloyl)pyrrolidin-2-yl)methyl)-5-((((S)-1-methoxypropan-2-yl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-3-(1-methylcyclopropyl)acryloyl)pyrrolidin-2-yl)methyl)-5-((((S)-1-methoxypropan-2-yl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((cyclopropylmethyl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(pyrimidin-4-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(1,2,4-oxadiazol-3-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(1H-1,2,4-triazol-1-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(1,2,4-oxadiazol-3-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-3-(1-methylcyclopropyl)acryloyl)pyrrolidin-2-yl)methyl)-5-(((2-hydroxy-2-methylpropyl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(4H-1,2,4-triazazol-3-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(((3,3-dimethylbutan-2-yl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(pyrimidin-4-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(2-fluoropyridin-4-yl)thiophene-2-carboxamide; 
 N-((E)-1-(((R)-1-((E)-2-cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(pyrazin-2-yl)thiophene-2-carboxamide; 
 N-((E)-1-(2-((E)-2-cyano-N,4,4-trimethylpent-2-enamido)-2-methylpropyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 (S,E)-N-(1-(2-(2-cyano-N-methylacrylamido)-2-methylpropyl)-5-(((3,3-dimethylbutan-2-yl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-((E)-1-(2-((E)-2-cyano-N,4-dimethylpent-2-enamido)-2-methylpropyl)-5-(((2-hydroxy-2-methylpropyl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 N-((E)-1-(2-((E)-2-cyano-4,4-dimethylpent-2-enamido)-2-methylpropyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 (S,E)-N-(1-(2-acrylamido-2-methylpropyl)-5-(((3,3-dimethylbutan-2-yl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(oxazol-5-yl)thiophene-2-carboxamide; and, 
 N-((E)-1-(((R)-1-((Z)-2-cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)methyl)-5-((((S)-3,3-dimethylbutan-2-yl)amino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)-5-(oxazol-5-yl)thiophene-2-carboxamide; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       10. A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. 
     
     
       11. A method of treating a disease treatable by inhibition of IL17 production in a mammal, where the disease is an autoimmune disease, an inflammatory disease or cancer, comprising administering to the mammal suffering from the disease, a pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof in a therapeutically effective amount and a pharmaceutically acceptable excipient. 
     
     
       12. The method of  claim 11  wherein the mammal is a human. 
     
     
       13. The method of  claim 12  wherein the disease is psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Behcet's disease, uveitis, keratitis, asthma, testitis, systemic lupus erythematosus, lupus nephritis, nephritis, chronic active hepatitis, Graft-versus-host disease, primary biliary cirrhosis, scleroderma, atopic dermatitis, nephrotic syndrome, pediatric autoimmune enteropathy, primary sclerosing cholangitis, pyoderma gangrenosum, alopecia universalis, or large granular lymphocyte leukemia. 
     
     
       14. A pharmaceutical composition comprising a compound of  claim 9 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. 
     
     
       15. A method of treating a disease treatable by inhibition of IL17 production in a mammal, where the disease in an autoimmune disease, an inflammatory disease or cancer, comprising administering to the mammal suffering from the disease, a pharmaceutical composition comprising a compound of  claim 9  or a pharmaceutically acceptable salt thereof in a therapeutically effective amount and a pharmaceutically acceptable excipient. 
     
     
       16. The method of  claim 15  wherein the mammal is a human. 
     
     
       17. The method of  claim 16  wherein the disease is psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Behcet's disease, uveitis, keratitis, asthma, testitis, systemic lupus erythematosus, lupus nephritis, nephritis, chronic active hepatitis, Graft-versus-host disease, primary biliary cirrhosis, scleroderma, atopic dermatitis, nephrotic syndrome, pediatric autoimmune enteropathy, primary sclerosing cholangitis, pyoderma gangrenosum, alopecia universalis, or large granular lymphocyte leukemia.